DESC:FIELD OF INVENTION
The present invention provides a prolonged release pharmaceutical composition of Ivabradine and pharmaceutically acceptable salts thereof. The present invention further provides a prolonged release pharmaceutical composition of Ivabradine and pharmaceutically acceptable salts thereof wherein, the said composition is intended for once a day administration. The invention further provides a simple, economical and less time-consuming process for preparation of prolonged release pharmaceutical composition of Ivabradine and pharmaceutically acceptable salts thereof.

BACKGROUND OF THE INVENTION
Ivabradine is a medication used for the symptomatic management of stable heart-related chest pain and heart failure not fully managed by beta blockers. The chemical name for Ivabradine is 3-(3-{[((7S)-3,4-Dimethoxybicyclo[4.2.0]octa-1,3,5-trien-7¬yl)methyl] methyl amino} propyl)-1,3,4,5-tetrahydro-7,8-dimethoxy-2H-3-benzazepin-2-one, hydrochloride. The molecular formula is C27H36N2O5, HCl, and the molecular weight (free base + HCl) is 505.1 (468.6 + 36.5). The chemical structure of Ivabradine is as follows:

Ivabradine is indicated for the symptomatic treatment of chronic stable angina pectoris in coronary artery disease in adults with normal sinus rhythm and heart rate = 70 bpm. Ivabradine is indicated in adults unable to tolerate or with a contra-indication to the use of beta-blockers or in combination with beta-blockers in patients inadequately controlled with an optimal beta-blocker dose.
There are several marketed formulations of immediate release Ivabradine or pharmaceutically acceptable salts thereof. However, under physiological conditions, when administered in a tablet dosage form, Ivabradine is rapidly released from tablet. Ivabradine is rapidly and almost completely absorbed after oral administration with a peak plasma level reached in about 1 hour under fasting condition. The absolute bioavailability of the film-coated tablets is around 40%, due to first-pass effect in the gut and liver.
However, there are certain drawbacks of administering the immediate release dosage forms of Ivabradine or pharmaceutically acceptable salts thereof, such as, a) the blood drug concentration increases vary fast eventually reducing the heart rate too fast and, b) the patient experiences symptoms related to bradycardia such as dizziness, fatigue or hypotension. Also, as Ivabradine has high solubility and is easily administered in blood, the peak plasma level of Ivabradine reaches in about 1 hour. Therefore, if given by prolonged release formulation, there is a risk of dose dumping in the blood.
Therefore, there is an unmet need for pharmaceutical composition of Ivabradine which provides the prolonged release of drug which maintains the blood drug concentration in therapeutic window for at least 24 hours and which do not impose the risk of dose dumping. The prolonged release formulation of present invention is prepared using direct compression method and was free from the dose dumping. Further, there is a need in the art for a process for preparing the prolonged release pharmaceutical composition of Ivabradine and pharmaceutical salts thereof for once a day administration, wherein the process is simple, economical and less time consuming.

OBJECTIVE OF THE INVENTION
According to one aspect, the present invention provides a prolonged release pharmaceutical composition of Ivabradine and pharmaceutically acceptable salts thereof.
In another aspect, the present invention provides a prolonged release pharmaceutical composition of Ivabradine and pharmaceutically acceptable salts thereof wherein, the said composition is intended for once a day administration.
In yet another aspect, the present invention provides a prolonged release pharmaceutical composition of Ivabradine and pharmaceutically acceptable salts thereof comprising at least one release controlling polymer and one or more pharmaceutical excipients.
In yet another aspect, the present invention provides a process for preparation of prolonged release pharmaceutical composition of Ivabradine and pharmaceutically acceptable salts thereof.
SUMMARY OF THE INVENTION
The present invention relates to a prolonged release pharmaceutical composition of Ivabradine or pharmaceutically acceptable salts for once a day administration wherein the said composition comprises:
(i) Ivabradine or pharmaceutically acceptable salts thereof;
(ii) at least one release controlling polymer; and
(iii) one or more pharmaceutical excipients.
The present invention also relates to a prolonged release pharmaceutical composition of Ivabradine or pharmaceutically acceptable salts for once a day administration wherein the said composition comprises:
(i) Ivabradine or pharmaceutically acceptable salts thereof;
(ii) at least one release controlling polymer; and
(iii) one or more pharmaceutical excipients;
wherein the composition is prepared using direct compression method.
The present invention further relates to a process for preparation of a prolonged release solid oral dosage form of pharmaceutical composition of Ivabradine or pharmaceutically acceptable salts thereof for once a day administration, comprising:
(i) sifting Ivabradine or pharmaceutically acceptable salts thereof, at least one rate controlling polymer and one or more pharmaceutical excipients;
(ii) mixing and blending the ingredients of step (i) to obtain a lubricated blend;
(iii) compressing the lubricated blend of step (ii) by direct compression technique to obtain the dosage form;
(iv) optionally film coating the dosage form obtained in step (iii).

DETAILED DESCRIPTION OF THE INVENTION
The present invention relates to a prolonged release pharmaceutical composition of Ivabradine and pharmaceutically acceptable salts thereof.
The term “Prolonged Release” herein refers to any formulation or dosage form that comprises an active drug and which is formulated to release the drug for longer duration of time and to provide a longer duration of pharmacological response after administration of the dosage form than is ordinarily not experienced after administration of a corresponding immediate release formulation comprising the same drug in the same amount.
Prolonged release formulations include, inter alia, those formulations described elsewhere as “controlled release”, “delayed release”, “sustained release”, “prolonged release”, “extended release”, “programmed release”, “time release” and/or “rate controlled” formulations or dosage forms. Further for the purposes of this invention refers to release of an active pharmaceutical agent over a prolonged period of time, such as for example over a period of 8, 12, 16 or 24 hours. By “pharmaceutically acceptable” is meant a carrier comprised of a material that is not biologically or otherwise undesirable.
The term “Ivabradine” as used in the invention is meant to cover Ivabradine in the form of freebase or its pharmaceutically acceptable salt(s), hydrate(s), solvate(s) and physiologically functional derivative(s) and precursors thereof. The term also includes all polymorphic forms, whether crystalline or amorphous.
In one embodiment, the present invention relates to a prolonged release pharmaceutical composition of Ivabradine or pharmaceutical salts thereof, which releases the drug from the composition for at least 24 hours.
In one embodiment, the present invention relates to a prolonged release pharmaceutical composition of Ivabradine or pharmaceutical salts thereof, which releases the drug from the composition for at least 16 hours.
In one embodiment, the present invention relates to a prolonged release pharmaceutical composition of Ivabradine or pharmaceutical salts thereof, which releases the drug from the composition for at least 12 hours.
In one embodiment, the present invention relates to a prolonged release pharmaceutical composition of Ivabradine or pharmaceutical salts thereof, which releases the drug from the composition for at least 8 hours.
In another embodiment, the present invention provides a prolonged release pharmaceutical composition of Ivabradine and pharmaceutically acceptable salts thereof, wherein said composition is intended for once a day administration.
In yet another embodiment, the present invention provides a prolonged release pharmaceutical composition of Ivabradine and pharmaceutically acceptable salts thereof, intended for once a day administration, wherein said composition is free from dose dumping.
The term ‘pharmaceutical composition’ can be alternatively referred as ‘pharmaceutical composition of Ivabradine or pharmaceutically acceptable salts’.
In yet another embodiment, the present invention provides a prolonged release pharmaceutical composition of Ivabradine or pharmaceutically acceptable salts for once a day administration wherein said composition comprises:
(i) Ivabradine or pharmaceutically acceptable salts thereof;
(ii) at least one release controlling polymer; and
(iii) one or more pharmaceutical excipients.
In yet another embodiment, the present invention provides a prolonged release pharmaceutical composition of Ivabradine or pharmaceutically acceptable salts for once a day administration wherein said composition comprises:
(i) Ivabradine or pharmaceutically acceptable salts thereof;
(ii) at least one release controlling polymer; and
(iii) one or more pharmaceutical excipients;
wherein the composition is prepared using direct compression method.
In one embodiment, Ivabradine or pharmaceutically acceptable salts thereof is present in the pharmaceutical composition in the range of 2% to 17% by weight. Preferably, the Ivabradine or pharmaceutically acceptable salts thereof is present in the range of 3% to 12% by weight.
In one embodiment, the release controlling polymers are present in the pharmaceutical composition in the range of 20% to 70% by weight. Preferably, the release controlling polymers are present in the range of 35% to 65% by weight.
In one embodiment, the pharmaceutical excipients are present in the pharmaceutical composition in the range of 20% to 80% by weight. Preferably, the pharmaceutical excipients are present in the range of 20% to 60% by weight.
In one embodiment, the present invention provides a prolonged release pharmaceutical composition of Ivabradine or pharmaceutically acceptable salts, wherein Ivabradine or pharmaceutically acceptable salts thereof and the release controlling polymer are present in a weight ratio between 1.0:2.0 and 1.0:15.0. More preferably, the weight ratio between Ivabradine or pharmaceutically acceptable salts thereof and the release controlling polymer is between 1.0:4.0 and 1.0:10.0.
In one embodiment, the tablet core can be optionally coated with a suitable coating material.
In yet another embodiment, the present invention provides a process for preparation of a prolonged release pharmaceutical composition of Ivabradine or pharmaceutically acceptable salts thereof for once a day administration.
In a preferred embodiment, the pharmaceutical composition was prepared by direct compression method.
In yet another embodiment, the present invention provides symptomatic treatment of chronic stable angina comprising administering a prolonged release pharmaceutical composition suitable for once daily dosing comprising Ivabradine or pharmaceutically acceptable salt thereof.
In one embodiment, the Ivabradine is preferably in the form of the hydrochloride.
In one embodiment, the release controlling polymer according to present invention include, but are not limited to, water soluble polymers such as hydroxyethyl cellulose, hydroxypropyl cellulose, carboxymethyl cellulose, hydroxypropylmethyl cellulose or hypromellose, sodium carboxymethyl cellulose, vinylpyrrolidone/vinyl acetate copolymer for example marketed as Plasdone® S-630, polyvinyl alcohol, polyethylene glycol and the like, Saccharides such as monosaccharides, disaccharides, oligosaccharides, polysaccharides or sugar alcohols which include but are not limited to sucrose, xylitol, mannitol, sorbitol, glucose, fructose, galactose, maltitol, lactose, maltodextrin, Water soluble organic acids, water soluble salts of organic acids, water soluble organic bases, water soluble salts of organic bases which include but are not limited to citric acid or salts thereof, amino acids or salt thereof, inorganic salts such as sodium carbonate, sodium bicarbonate, potassium chloride and sodium chloride, polyvinyl acetate dispersion, ethyl cellulose, cellulose acetate, cellulose propionate (lower, medium or higher molecular weight), cellulose acetate propionate, cellulose acetate butyrate, cellulose acetate phthalate, cellulose triacetate, poly(methyl methacrylate), poly (ethyl methacrylate), poly(butyl methacrylate), poly(isobutyl methacrylate), and poly (hexyl methacrylate), poly(isodecyl methacrylate), poly(lauryl methacrylate), poly (phenyl methacrylate), poly(methyl acrylate), poly(isopropyl acrylate), -poly (isobutyl acrylate), poly(octadecyl acrylate), waxes such as beeswax, carnauba wax, paraffin wax, microcrystalline wax, and, ozokerite; fatty alcohols such as cetostearyl alcohol, stearyl alcohol, cetyl alcohol and myristyl alcohol, and fatty acid esters such as glyceryl monostearate; glycerol monooleate, acetylated monoglycerides, tristearin, tripalmitin, cetyl esters wax, glyceryl palmitostearate, glyceryl behenate, and hydrogenated vegetable oils and such.
In a preferred embodiment, the release controlling polymers are selected from the group consisting of hypromellose, polyvinyl acetate, polyvinylpyrrolidone, hydroxyethyl cellulose, hydroxypropylcellulose, or a combination thereof.
The pharmaceutical compositions according to present invention will, in general comprise of one or more excipients. Examples of pharmaceutical excipients include, but are not limited to binders, fillers or diluents, lubricants, glidants, disintegrants. A combination of excipients may also be used. The amount of excipient(s) employed will depend upon how much active agent is to be used. One excipient can perform more than one function.
In one embodiment, the coating material can be selected from, but not limited to, hypromellose, polyethylene glycol, glycerine, yellow iron oxide, red iron oxide titanium dioxide, polyvinyl alcohol, talc, or a combination thereof.
In one embodiment, the coating material is selected from ColoRezy 17G530007 Orange or Opadry II.
The present invention further provides a simple, cost effective and less time-consuming process for preparation of prolonged release pharmaceutical composition of Ivabradine and pharmaceutically acceptable salts thereof.
In one embodiment, the present invention provides a process for preparation of a prolonged release pharmaceutical solid oral dosage form of Ivabradine or pharmaceutically acceptable salts thereof for once a day administration, wherein the process comprises following steps:
(i) sifting Ivabradine or pharmaceutically acceptable salts thereof, at least one rate controlling polymer and one or more pharmaceutical excipients;
(ii) mixing and blending the ingredients of step (i) to obtain a lubricated blend ;
(iii) compressing the lubricated blend of step (ii) by direct compression technique to obtain the dosage form;
(iv) optionally film coating the dosage form obtained in step (iii).
In another embodiment, the present invention provides a process for preparation of a prolonged release pharmaceutical solid oral dosage form of Ivabradine or pharmaceutically acceptable salts thereof, wherein Ivabradine or pharmaceutically acceptable salts thereof is present in range of 2% to 17% by weight. Preferably, the Ivabradine or pharmaceutically acceptable salts thereof is present in the range of 3% to 12% by weight.
In yet another embodiment, the present invention provides a process for preparation of a prolonged release pharmaceutical solid oral dosage form of Ivabradine or pharmaceutically acceptable salts thereof, wherein the release controlling polymers are present in the range of 20% to 70% by weight. Preferably, the release controlling polymers are present in the range of 35% to 65% by weight.
In one embodiment, the present invention provides a process for preparation of a prolonged release pharmaceutical solid oral dosage form of Ivabradine or pharmaceutically acceptable salts thereof, wherein the pharmaceutical excipients are present in the range of 20% to 80% by weight. Preferably, the pharmaceutical excipients are present in the range of 20% to 60% by weight.
In one embodiment, the present invention provides a process for preparation of a prolonged release pharmaceutical solid oral dosage form of Ivabradine or pharmaceutically acceptable salts thereof, wherein Ivabradine or pharmaceutically acceptable salts thereof and the release controlling polymer are present in a weight ratio between 1.0:2.0 and 1.0:15.0. More preferably, the weight ratio between Ivabradine or pharmaceutically acceptable salts thereof and the release controlling polymer is between 1.0:4.0 and 1.0:10.0.
In one embodiment, the prolonged release pharmaceutical composition of Ivabradine or pharmaceutically acceptable salts is obtained from the claimed process.
In yet another embodiment, the pharmaceutical composition is in the form of solid oral dosage form such as tablet, capsule, granules, sachet, a tablet with or without coating, bilayer tablet, functional coated tablets or caplets, time-release tablets or caplets, floating tablets, matrices containing polymer, controlled release beads, granules, spheroids that are contained within a capsule of administered from sachet of other unit dose powder device in combination with other beneficial drugs or as a combination kit of prolonged release dosage forms for the administration in mammals.
In another preferred embodiment, the pharmaceutical composition is in the form of prolonged release tablet. The tablets according to present invention can be prepared by processes well known to those of skill in the art. For example, core tablets can be prepared by direct compression, wet granulation, dry granulation, melt granulation and the like.
Binders include, but are not limited to, starches such as potato starch, wheat starch, corn starch; microcrystalline cellulose such as products known under the registered trademarks Avicel, Filtrak, Heweten or Pharmacel; celluloses such as hydroxypropyl cellulose, hydroxyethyl cellulose, hydroxypropylmethylcellulose (HPMC), ethyl cellulose, sodium carboxymethylcellulose; natural gums like acacia, alginic acid, guar gum; liquid glucose, dextrin, povidone, syrup, polyethylene oxide, polyvinylpyrrolidone, poly-N-vinyl amide, polyethylene glycol, gelatin, poly propylene glycol, tragacanth, combinations thereof and other materials known to one of ordinary skill in the art and mixtures thereof.
Fillers or diluents, which include, but are not limited to confectioner's sugar, compressible sugar, dextrates, dextrin, dextrose, fructose, lactitol, mannitol, sucrose, starch, lactose, xylitol, sorbitol, talc, microcrystalline cellulose, calcium carbonate, calcium phosphate dibasic or tribasic, calcium sulphate, and the like can be used.
Lubricants may be selected from, but are not limited to, those conventionally known in the art such as Mg, Al or Ca or Zn stearate, polyethylene glycol, glyceryl behenate, mineral oil, sodium stearyl fumarate, stearic acid, hydrogenated vegetable oil and talc.
Glidants include, but are not limited to, silicon dioxide; magnesium trisilicate, powdered cellulose, starch, talc and tribasic calcium phosphate, calcium, silicate, magnesium silicate, colloidal silicon dioxide, silicon hydrogel and other materials known to one of ordinary skill in the art.
Disintegrants include, but are not limited to: alginic acid, carboxymethylcellulose calcium, carboxymethylcellulose sodium, croscarmellose sodium, crospovidone, guar gum, magnesium aluminium silicate, sodium alginate, sodium starch glycolate and starches and other materials known to one of ordinary skill in the art and combinations thereof.
The following examples illustrate preferred embodiments in accordance with the present invention without limiting the scope or spirit of the invention.

Example 1: Batch No. 001
Table 1
Batch No. 001
Ingredient %w/w
Intra granular ingredients
Ivabradine Hydrochloride eq. to. Ivabradine 15 mg 8.09
Hypromellose 50.00
Lactose Monohydrate 40.91
Isopropyl Alcohol q.s.
Extra granular ingredients
Magnesium Stearate 1.00
Total 100.00

Manufacturing Process:
1. Ivabradine Hydrochloride, Hypromellose and Lactose Monohydrate were sifted through 40# sieve and mixed in rapid mixer granulator for 15 minutes.
2. Mixture of step 1 was granulated by adding Isopropyl alcohol.
3. The wet granules obtained in step 2 were dried to get LOD between 2-3%.
4. The dried granules of step 3 were passed through sieve # 30.
5. Magnesium stearate was passed through sieve # 60, and mixed with step 4 granules for 2 minutes.
6. The lubricated granules of step 5 were compressed in tablets.
7. The dissolution of tablets was determined in 900 ml, 0.1N HCl, USP Type I, 50 RPM.
Table 2
Dissolution 900 ml 0.1N HCl, USP Type I, 50 RPM
Batch No. 001
Time (Hours) % Drug Released
1 23
2 35
4 47
6 59
8 68
10 77
12 85
16 95
20 101
24 104

Example 2: Batch No.002, 003, 004, 005, 006, 007 and 008
Table 3
Batch No 002 003 004 005 006 007 008
Ingredients %w/w %w/w %w/w %w/w %w/w %w/w %w/w
Ivabradine Hydochloride eq. to. Ivabradine 15 mg/ 10 mg 8.09 8.09 5.39 8.09 8.09 8.09 8.09
Dibasic Calcium Phosphate Anhydrous 35.91 40.91 43.61 38.41 65.91 60.91 50.91
Hypromellose 55.00 50.00 50.00 52.50 25.00 30.00 40.00
Magnesium Stearate 1.00 1.00 1.00 1.00 1.00 1.00 1.00
Total 100 100 100 100 100 100 100

Manufacturing Process:
1. Ivabradine Hydrochloride, Dibasic Calcium Phosphate Anhydrous and Hypromellose were sifted through 40# sieve and mixed.
2. Magnesium stearate was sifted through sieve # 60, and added to step 1 mixture and mixed for 1 minute 30 seconds.
3. The lubricated blend of step 2 was compressed into tablets.
4. The dissolution of tablets was determined in 900 ml, 0.1N HCl, USP Type I, 50 RPM.

Table 4
Batch No 002 003 004 005 006 007 008
Dissolution 900 ml, 0.1N HCl, Basket, 50 rpm
Time (Hours) % Drug released
1 21 25 23 23 33 26 26
2 33 39 36 35 48 41 41
4 50 59 55 54 69 66 64
6 64 74 70 69 84 83 81
8 74 84 81 79 92 91 91
10 80 91 88 86 95 96 98
12 84 95 93 90 96 98 102
16 90 100 98 96 96 98 105
20 92 102 99 98 96 98 107
24 93 103 100 98 96 97 105

Dissolution of Batch no. 003 was determined in different dissolution media.
Table 5
Batch No. 003
Dissolution Condition 900 ml, USP Type I (Basket), 50 RPM
Media 0.1 N HCl pH 4.5 pH 6.8 Water 0.1N HCl (2 Hours) followed by pH 6.8 40% Alcohol in 0.1N HCl
Time (Hours) Cumulative % Drug Release
0.5 16 16 15 15 15 16
1 25 24 25 28 25 23
2 39 37 38 43 38 34
4 59 56 51 63 51 51
6 74 70 67 77 67 63
8 84 81 77 87 77 73
10 91 89 85 93 85 81
12 95 95 90 98 90 87
16 100 103 97 108 97 94
20 102 107 100 - - 99
24 103 110 102 - - 101

Example 3: Batch No. 009
Table 6
Batch No. 009
Ingredient %w/w
Intra granular ingredients
Ivabradine Hydrochloride eq. to. Ivabradine 15 mg 8.09
Lactose Anhydrous 35.91
Polyvinyl acetate/polyvinylpyrrolidone 55.00
Extra granular ingredients
Magnesium Stearate 1.00
Total 100.00

Manufacturing Process:
1. Ivabradine Hydrochloride, Polyvinyl acetate/polyvinylpyrrolidone and Lactose anhydrous were sifted through 40# sieve and mixed in blender for 20 minutes.
2. Magnesium stearate was sifted through sieve # 60, and added to step 1 mixture and mixed for 1 minute 30 seconds.
3. The lubricated blend of step 2 was compressed into tablets.
Table 7
Dissolution 900 ml 0.1N HCl, USP Type I, 50 RPM
Batch No. 009
Time (Hours) % Drug Released
1 37
2 50
4 71
6 88
8 97
10 101
12 103
16 105

Example 4: Batch No. 010
Table 8
Batch No 010
Ingredients %w/w
Ivabradine Hydrochloride eq. to. Ivabradine 15 mg 8.09
Lactose Anhydrous 40.91
Hypromellose 50.00
Magnesium Stearate 1.00
Total 100.0

Brief Manufacturing Process:
1. Ivabradine Hydrochloride, Dibasic Calcium Phosphate Anhydrous and Hypromellose were sifted through 40# sieve and mixed.
2. Magnesium stearate was sifted through sieve # 60, and added to step 1 mixture and mixed for 1 minute 30 seconds.
3. The lubricated blend of step 2 was compressed into tablets.
4. The dissolution of tablets was determined in 900 ml, 0.1N HCl, USP Type I, 50 RPM.
Table 9
Batch No 010
Dissolution 900 ml, 0.1N HCl, USP Type I, 50 RPM
Time (Hours) % Drug released
1 23
2 35
4 53
6 67
8 77
10 84
12 88
16 94
20 99
24 98

Example 5: Batch No. 011, 012, 013, 014
Table 10
Batch No. 011 012 013 014
Ingredient %w/w %w/w %w/w %w/w
Ivabradine Hydrochloride eq. to. Ivabradine 15 mg 7.81 8.09 8.09 8.04
Anhydrous dibasic Calcium Phosphate 40.01 41.41 41.41 -21.31
Hypromellose 48.31 - - -
Hypromellose - 50.00 - -
Hypromellose - - 50.00 49.75
Hypromellose - - 19.90
Magnesium Stearate 0.97 1.00 1.00 1.00
Total - 100 100 100
ColoRezy 17G530007 Orange 2.90 - - -
Purified Water - - - -
Total weight of coated tablet 100 - - -

Manufacturing Process:
1. Ivabradine Hydrochloride, Dibasic Calcium Phosphate Anhydrous and Hypromellose were sifted through 40# sieve and mixed.
2. Magnesium stearate was sifted through sieve # 60, and added to step 1 mixture and mixed for 1 minute 30 seconds.
3. The lubricated blend of step 2 was compressed into tablets.
4. Compressed tablets of 011 were coated with the aqueous dispersion of ColoRezy 17G530007 Orange.
5. The dissolution of tablets was determined in 900 ml, 0.1N HCl, USP Type I, 50 RPM.
Table 11
Dissolution condition 900 ml, 0.1N HCl, USP Type I, 50 RPM
Batch No. 011 012 013 014
Time (Hours) % Drug Released
1 23 16 15 16
2 37 27 25 26
4 58 45 41 41
6 73 60 53 48
8 84 71 63 63
10 91 81 72 72
12 95 88 79 79
16 99 95 88 88

Dissolution of batch 011 was determined in 0.1N HCl, pH 4.5 and pH 6.8
Table 12
Batch No. 011
Dissolution Media 0.1N HCl pH 4.5 pH 6.8
Dissolution Condition Volume 900 ml, apparatus basket, 50 RPM
Time (Hours) Drug Release (%)
1 23 23 20
2 37 35 44
4 58 51 60
6 73 64 73
8 84 73 82
10 91 80 88
12 95 86 93

Example 6: Batch No. 015
Table 13
Batch No. 015
Ingredient %w/w
Ivabradine Hydrochloride eq. to. Ivabradine 10 mg 7.81
Dibasic Calcium Phosphate Anhydrous 40.01
Hypromellose 48.31
Magnesium Stearate 0.97
Total -
ColoRezy 17G530007 Orange 2.90
Purified Water -
Weight of coated tablet 100.0

Manufacturing Process:
1. Ivabradine Hydrochloride, Dibasic Calcium Phosphate Anhydrous and Hypromellose were sifted through 40# sieve and mixed.
2. Magnesium stearate was sifted through sieve # 60, and added to step 1 mixture and mixed.
3. The lubricated blend of step 2 was compressed into tablets.
4. Compressed tablets of step 3 were coated with the aqueous dispersion of ColoRezy 17G530007 Orange.
Table 14
Batch No. 015
Dissolution Media 0.1N HCl pH 4.5 pH 6.8
Dissolution Condition: Volume 900 ml, apparatus basket, 50 RPM
Time (Hours) Drug Release (%)
1 25 27 27
2 38 42 42
4 59 64 61
6 74 78 76
8 84 90 86
10 93 98 92
12 94 101 98

Example 7: Batch No. 016
Table 15
Batch No. 016
Ingredients %w/w
Ivabradine Hydrochloride eq. to. Ivabradine 15 mg 7.81
Dibasic Calcium Phosphate Anhydrous 40.01
Hypromellose 48.31
Magnesium Stearate 0.97
Weight of uncoated tablet -
ColoRezy 17G530007 Orange 2.90
Purified Water -
Weight of coated tablet 100

Manufacturing Process:
1. Ivabradine Hydrochloride, Dibasic Calcium Phosphate Anhydrous and Hypromellose were sifted through 40# sieve and mixed in blender for 20 minutes.
2. Magnesium stearate was sifted through sieve # 60, and added to step 1 mixture and mixed for 3 minutes.
3. The lubricated blend of step 2 was compressed into tablets.
4. Compressed tablets of step 3 were coated with the aqueous dispersion of ColoRezy 17G530007 Orange.
Table 16
Batch No. 016
Dissolution 900 ml, 0.1N HCl, USP Type I, 50 RPM
Time (Hours) % Drug released
1 24
2 38
4 58
6 73
8 83
10 89
12 93

While the invention has been described and illustrated with reference to certain particular embodiments thereof, those skilled in the art will appreciate that various adaptations, changes, modifications, substitutions, deletions, or additions of procedures and protocols may be made without departing from the spirit and scope of the invention. For example, effective dosages other than the particular dosages as set forth herein above may be applicable as a consequence of variations in responsiveness of the mammal being treated for any of the indications with the compounds of the invention indicated above. The specific pharmacological responses observed may vary according to and depending upon the particular active compounds selected or whether there are present pharmaceutical carriers, as well as the type of formulation and mode of administration employed, and such expected variations or differences in the res tills arc contemplated in accordance with the objects and practices of the present invention. It is intended, therefore, that the invention be defined by the scope of the claims which follow and that such claims be interpreted under their broadest reasonable interpretation in view of this specification.

,CLAIMS:1. A prolonged release pharmaceutical composition of Ivabradine or pharmaceutically acceptable salts for once a day administration, wherein the composition comprises:
(iv) Ivabradine or pharmaceutically acceptable salts thereof;
(v) at least one release controlling polymer; and
(vi) one or more pharmaceutical excipients.

2. A prolonged release pharmaceutical composition of Ivabradine or pharmaceutically acceptable salts for once a day administration, wherein the composition comprises:
(iv) Ivabradine or pharmaceutically acceptable salts thereof;
(v) at least one release controlling polymer; and
(vi) one or more pharmaceutical excipients;
wherein the composition is prepared using direct compression method.

3. The pharmaceutical composition as claimed in claim 1 or 2, wherein the release controlling polymer is present in the range of 20% to 70% by weight.

4. The pharmaceutical composition as claimed in claim 1 or 2, wherein the Ivabradine or pharmaceutically acceptable salts thereof is present in the range of 2% to 17% by weight.

5. The composition as claimed in claim 1 or 2, wherein the Ivabradine or pharmaceutically acceptable salts thereof and the release controlling polymer are present in a weight ratio between 1.0:2.0 and 1.0:15.0.

6. The pharmaceutical composition as claimed in claim 1 or 2, wherein the release controlling polymer is selected from water soluble polymers, water soluble organic acids, water soluble salts of organic acids, water soluble organic bases, water soluble salts of organic bases, fatty alcohols, fatty acid esters, or combination thereof.

7. The pharmaceutical composition as claimed in claim 6, wherein the release controlling polymer is selected from hypromellose, polyvinyl acetate, polyvinylpyrrolidone, hydroxyethyl cellulose, hydroxypropylcellulose, or a combination thereof.

8. The composition as claimed in claim 1 or 2, wherein the one or more excipients are selected from binders, fillers, diluents, lubricants, glidants, disintegrants, or a combination thereof.

9. A process for preparation of a prolonged release solid oral dosage form of pharmaceutical composition of Ivabradine or pharmaceutically acceptable salts thereof for once a day administration, the process comprising:
(i) sifting Ivabradine or pharmaceutically acceptable salts thereof, at least one rate controlling polymer and one or more pharmaceutical excipients;
(ii) mixing and blending the ingredients of step (i) to obtain a lubricated blend;
(iii) compressing the lubricated blend of step (ii) by direct compression technique to obtain the dosage form;
(iv) optionally film coating the dosage form obtained in step (iii).

10. The process as claimed in claim 9, wherein the dosage form is in the form of tablet, capsule, granules, or sachet.